Understanding the processes which result in long-term immunological memory is required for the effective development of vaccines and for gaining insight into the mechanisms controlling immunity versus tolerance. Mucosal tissue represents a critical barrier to invasion by potential pathogens. This application focuses on determining the requirements for induction and maintenance of CD8 T-cell memory in the small and large intestinal mucosa. Using a sensitive T-cell adoptive transfer system to track CD8 T-cells in vivo they are now able to analyze the generation and control of mucosal T-cell memory. Preliminary results suggest that mucosal memory T-cells are derived from peripheral T-cells and that induction of mucosal T-cell responses may exhibit unique co-stimulatory requirements. Novel transgenic mice have also been developed to study the concept of tissue-specific T-cell memory versus systemic memory. Finally, intriguing preliminary studies suggest that T-cell receptor gamma/delta (TCRgd) T-cells play an integral role in controlling TCR alpha/beta (TCRab) T-cell responses and in this way effect long-term CD8 T-cell memory. The aims of the application are: Aim 1: To define the immunological parameters necessary for generation of CD8 T-cell memory in the intestinal mucosa. Aim 2: To determine the requirements for costimulation in generation of memory and in reactivation of CD8 mucosal memory T-cells. Aim 3: To determine the consequences of mucosal antigen presentation on generation and maintenance of intestinal CD* T-cell memory. Aim 4: To determine the role of TCRgd T-cells in regulation of TCRab CD8 T-cell responses and memory T-cell production. The proposed studies will provide much needed information regarding the requirements for establishing long-term T-cell memory in the intestinal mucosa.